The objective of this application is to elucidate in more detail, the mechanism of action of these drugs of abuse, especially in how they interact with central cholinergic systems. Recent evidence from our laboratory has shown that the intraventricular injection of acetylcholine produces antinociception and interacts with opiate receptors similar to those produced by parenterally adminstered morphone. The 1-isomers of cyclazocine and potazocine block the antinociceptive and opiate receptor binding activity of morphine but were inactive versus the antinociception and opiate receptor binding induced by acetylcholine which in turn was blocked by the d-isomer of these antagonists. We will investigate the similarities and differences between changes in cholinergic mechanisms induced by morphine and those induced by intraventricular acetylcholine. It is becoming increasingly more apparent that morphine and other narcotic analgesics block the release of acetylcholine and this may be an important factor in their mechanism of action. Recently, it has been shown that delta-9-THC and other cannabinoids also inhibit the release of this amine. We propose to inestigate the effects of opiates on the release of acetylcholine at cholinergic synapses in the central nervous system. We propose to test the hypothesis that the release of acetylcholine is blocked in a stereospecific manner by opiates, only at those central neurons which release acetylcholine upon muscarinic receptors. We have recently devised a method for measuring acetylcholine turnover rate in one or two mg samples of brain tissue. We propose to study the effects of drugs of abuse on various brain parts utilizing this technique. BIBLIOGRAPHIC REFERENCES: Forbes, J.E. and Dewey, W.L.: The effects of narcotic analgesics and narcotic antagonists on ganglionic trasmission in the rat. Life Sciences 19:401-408, 1976. Dewey, W.L., Chau-Pham, T.T., and Cocolas, G.C.: The antinociceptive effects of acetylcholine analogs and isomers and their antagonism by isomers of narcotic antagonists. Elsevier/North-Holland and Biomedical Press, Amsterdam, The Netherlands, Opiates and Endogenous Opiod Peptides, 185, 190, 1976.